Table 1. Drug interactions of caffeine and herbal drugs containing caffeine.
| ATC therapeutic subgroup | ATC pharmacological/chemical subgroup | Drugs | Pharmacokinetic basis of interaction | Pharmacodynamic basis of interaction | Manifestation of interaction | |
|---|---|---|---|---|---|---|
| Stomatological preparations (A01) | Vasoconstrictors | Epinephrine (Adrenaline) | CYP1A2 | Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. | additive (psychostimulant) effect ↑ adverse reactions (hypertension, myocardial infarction, stroke, seizures) ! reduce/restrict caffeine intake |
Van Soeren et al. (1996) |
| CYP3A4 | ||||||
| Antihemorrhagics (B02) | Local hemostatics | |||||
| Cardiac therapy (C01) | Adrenergic agents | |||||
| Nasal preparations (R01) | Decongestants and other nasal preparations for topical use Sympathomimetics, plain |
|||||
| Drugs for obstructive airway diseases (R03) | Adrenergic inhalants, alpha- and beta-adrenoreceptor agonists | |||||
| Ophtalmologicals (S01) | Sympathomimetics in glaucoma therapy | |||||
| Stomatological preparation, in dentistry (A01) | Salicylic acid and derivatives | Acetylsalicylic acid | CYP1A2 CYP2C9 CYP3A4 |
↑ bioavailability ↑ analgetic effect |
Diener et al. (2005) | |
| Antithrombotic agents (B01) | ||||||
| Analgetics (N02) | ||||||
| Drugs for acid related disorders (A02) | H2-receptor antagonists | Cimetidine | CYP2C9 |
↑ caffeine plasma level ↓ caffeine clearance (31–42%) ↑ caffeine adverse reactions ! reduce/restrict caffeine intake |
Broughton & Rogers (1981) | |
| Proton pump inhibitors | Omeprazol | CYP2C9 |
↑ caffeine plasma level ↓ caffeine clearance ↑ caffeine adverse reactions ! reduce/restrict caffeine intake |
Andersson et al. (1998) | ||
| Antiobesity preparations, excl. diet products (A08) | Centrally acting antiobesity products | Amfepramone Phentermine | CYP1A2 CYP3A4 |
Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. | additive (psychostimulant) effect ↑ adverse reactions (hypertension, myocardial infarction, stroke, seizures) ! reduce/restrict caffeine intake |
Solimini et al. (2017) |
| Antiobesity preparations, excl. diet products (A08) | Centrally acting antiobesity products | Ephedrine (orally) | CYP1A2 CYP3A4 |
Caffeine is a competitive adenosine antagonist and releases endogenous catecholamines. | additive effect ! life-threatening risk (hypertension, myocardial infarction, stroke, seizures, even death) ! reduce/restrict caffeine intake |
Astrup et al. (1992) |
| Cardiac therapy (C01) | Adrenergic and dopaminergic agents | |||||
| Nasal preparations (R01) | Decongestants and other nasal preparations for topical use; sympathomimetics, plain Sympathomimetics, combinations excl. corticosteroids |
|||||
| Drugs for obstructive airway diseases (R03) | Alpha- and beta-adrenoreceptor agonists | |||||
| Ophthalmologicals (S01) | Sympathomimetics excl. antiglaucoma preparations | |||||
| Drugs used in diabetes (A10) | Blood glucose lowering drugs, excl. insuline, sulfonylureas | Glibornuride Glimepiride |
CYP2C9 | Glucose tolerance affected. | glucose level affected ! monitor glucose level(s) |
Czigle & Tóth (2016), Williamson, Driver & Baxter (2018) |
| Blood glucose lowering drugs, excl. insuline, thiazolidinedione | Pioglitazone Rosiglitazone |
CYP2C9 | Glucose tolerance affected. | glucose level affected ! monitor glucose level(s) |
Czigle & Tóth (2016), Williamson, Driver & Baxter (2018) | |
| Antithrombotic agents (B01) | Platelet aggregation inhibitors excl. heparin | Clopidogrel Dipyridamole Ticlopidine |
CYP1A2 CYP2D6 |
Caffeine is a competitive adenosine antagonist. |
↑ bioavailability ↑ antithrombotic effect ! bleeding risk ! do not use combination (24 h interval) |
Birnbaum et al. (2015) |
| Vitamin K antagonists | Warfarin | CYP1A2 CYP2C9 |
↑ anticoagulant effect ! bleeding risk ! reduce/restrict caffeine intake |
Anthony et al. (2009) | ||
| Heparin group | Ardeparin Dalteparin Enoxaparin Heparin |
CYP1A2 CYP2C9 |
↑ anticoagulant effect ! bleeding risk ! reduce/restrict caffeine intake Ardeparin was recalled from circulation for reasons unrelated to safety or efficacy |
Anthony et al. (2009) | ||
| Cardiac therapy (C01) | Antiarrhythmics, class Ib | Lidocaine Mexiletine Tocainide |
CYP1A2 CYP2D6 |
Caffeine is a competitive adenosine antagonist. |
↑ caffeine plasma level ↑ caffeine adverse reactions ! reduce/restrict caffeine intake |
Amjad et al. (2017), Czigle & Tóth (2016) |
| Antiarrhythmics, class Ic | Flecainide | CYP2D6 | Caffeine is a competitive adenosine antagonist. |
↑ caffeine plasma level ↑ caffeine adverse reactions ! reduce/restrict caffeine intake |
Hwang et al. (2019) | |
| Antifungals for dermatological use (D01) | Antifungals for systemic use/allylamine antifungals | Terbinafine | CYP1A2 CYP3A4 |
↑ caffeine plasma level ↓ caffeine clearance (19%) ↑ caffeine effect prolongation ! reduce/restrict caffeine intake |
Trépanier, Nafziger & Amsden (1998) | |
| Sex hormones and modulators of the genital system (G03) | Hormonal contraceptives for systemic use | Ethinylestradiol (EE), Estradiol + progestogens |
CYP1A2 CYP2C9 CYP3A4 |
Estrogens are inhibitors of caffeine metabolism. |
↑ caffeine plasma level ↓ caffeine clearance (40–65%) ! reduce/restrict caffeine intake |
Fantoli (1981), Patwardhan et al. (1980) |
| Antibacterials for systemic use (J01) | Quinolone antibacterials | Ciprofloxacin Clinafloxacin Enoxacin Gatifloxacin Grepafloxacin Levofloxacin Lomefloxacin Moxifloxacin Norfloxacin Ofloxacin Pipemidic acid Rufloxacin Sparfloxacin Trovafloxacin |
CYP1A2 CYP3A4 |
↑ caffeine plasma level ↓ caffeine metabolism (N-demethylation) ↓ caffeine clearance ↑ adverse reactions ! reduce/restrict caffeine intake |
Czigle & Tóth (2010b), Woziwodzka et al. (2022) | |
| Antimycotics for systemic use (J02) | Triazole and tetrazole derivatives—antimycotics | Fluconazol | CYP1A2 CYP3A4 |
↓ caffeine clearance (25%) ! reduce/restrict caffeine intake |
Czigle & Tóth (2010b) | |
| Drugs for treatment of bone diseases (M05) | Drugs affecting bone structure and mineralization, bisphosphonates | Alendronic acid | CYP1A2 CYP3A4 |
↓ bioavailability ! reduce/restrict caffeine intake (2 h interval) |
Czigle & Tóth (2010b) | |
| Analgesics (N02) | Other analgesics and antipyretics, anilides | Paracetamol | CYP1A2 CYP3A4 CYP2E1 |
↑ bioavailability ↑ analgetic effect |
Diener et al. (2005), Granados-Soto & Castañeda-Hernández (1999), Zhang (2001) | |
| Antimigraine preparations, ergot alkaloids | Ergotamine | CYP1A2 CYP3A4 |
Caffeine vigilance increased. |
↑ absorbance ! reduce/restrict caffeine intake |
Granados-Soto & Castañeda-Hernández (1999) | |
| Antiepileptics (N03) | Antiepileptics, barbiturates and derivatives | Phenobarbital | CYP2C9 | Caffeine vigilance increased. |
↓ plasma level ↓ anticonvulsive effect ! reduce/restrict caffeine intake |
Chrościńska-Krawczyk et al. (2014), Jankiewicz et al. (2007) |
| Antiepileptics, hydantoin derivatives | Phenytoin | CYP1A2 CYP3A4 |
Caffeine vigilance increased. |
↓ plasma level ↓ anticonvulsive effect ! reduce/restrict caffeine intake |
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019) | |
| Antiepileptics, benzodiazepine derivatives | Clonazepam | CYP1A2 CYP3A4 |
Caffeine vigilance increased. |
↓ plasma level ↓ anticonvulsive effect ! reduce/restrict caffeine intake |
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019) | |
| Antiepileptics, carboxamide derivatives | Carbamazepine | CYP3A4 CYP2C8 |
Caffeine vigilance increased. |
↓ plasma level ↓ anticonvulsive effect ! reduce/restrict caffeine intake |
Chrościńska-Krawczyk et al. (2014), Jankiewicz et al. (2007), Nomani et al. (2019) | |
| Antiepileptics, fatty acid derivatives | Valproic acid | CYP2C9 CYP2A6 |
Caffeine vigilance increased. |
↓ plasma level ↓ anticonvulsive effect ! reduce/restrict caffeine intake |
Chrościńska-Krawczyk et al. (2014), Nomani et al. (2019) | |
| Psycholeptics (N05) | Antipsychotics | Clozapine Fluphenazine Haloperidol Chlorpromazine Lithium Prochlorperazine Thioridazine Triflupromazine |
CYP1A2 CYP2D6 |
Caffeine vigilance increased. |
↑ clozapine plasma level ↑ clozapine toxicity (400–1,000 mg caffeine per day) ↓ lithium plasma level (tremor possible after abrupt caffeine withdrawal) ! exacerbation of psychotic symptoms (possible) ! reduce/restrict caffeine intake ! patient monitoring necessary |
Carrillo & Benitez (2000) |
| Anxiolytics, benzodiazepine derivatives | Alprazolam Diazepam |
CYP1A2 CYP3A4 |
Caffeine vigilance increased. |
↓ plasma level ↓ anxiolytic effect ! reduce/restrict caffeine intake |
Loke, Hinrichs & Ghoneim (1985), Roache & Griffiths (1987) | |
| Hypnotics and sedatives | Pentobarbital Triazolam Zolpidem Zopiclon |
CYP2C2 | Caffeine vigilance increased. |
↓ hypnotic effect ! reduce/restrict caffeine intake |
Batéjat et al. (2006), Walsh, Muehlbach & Schweitzer (1995) | |
| Melatonin receptor agonists | Melatonin | Harpsøe et al. (2015), Härtter et al. (2006) | ||||
| Psychoanaleptics (N06) | Antidepressants, non-selective monoamine reuptake inhibitors | Amitriptyline Imipramine |
CYP1A2 CYP2C19 |
Caffeine vigilance increased. |
↑ caffeine plasma level ↑ adverse reactions ! reduce/restrict caffeine intake |
Sawynok (2011) |
| Antidepressants, selective serotonin reuptake inhibitors | Fluvoxamine | CYP1A2 CYP2C19 |
Caffeine vigilance increased. |
↑ caffeine plasma level ↑ adverse reactions ! reduce/restrict caffeine intake |
Carrillo & Benitez (2000) | |
| Other nervous system drugs (N07) | Drugs used in nicotine dependence | Nicotine (transdermally) |
CYP2C9 |
↑ of caffeine plasma level ↓ caffeine clearance ! exclude caffeine (intoxication risk) |
Kroon (2007) | |
| Drugs used in alcohol dependence | Disulfiram | CYP1A2 CYP3A4 |
↑ caffeine plasma level ↓ caffeine clearance ! exclude caffeine (intoxication risk) |
Beach et al. (1986) | ||
| Other nervous system drugs, multiple sclerosis treatment | Riluzole | CYP1A2 | Caffeine vigilance increased. |
↑ caffeine and riluzole plasma level ! reduce/restrict caffeine intake |
van Kan et al. (2005) | |
| Nasal preparations (R01) | Sympathomimetics | Phenylpropanolamine Pseudoephedrine |
CYP1A2 | Caffeine vigilance increased. |
↑ caffeine plasma level ↑ adverse reaction (hypertension) ! dosage adjustment |
Jones (2008), Pentel (1984) |
| Drugs for obstructive airway diseases (R03) | Non-selective beta-adrenoreceptor agonists) | Isoprenaline (Isoproterenol) Orciprenaline (Metaproterenol) |
CYP1A2 |
↑ positive inotropic effect of β-sympathomimetics ! reduce/restrict caffeine intake |
Czigle & Tóth (2010b) | |
| Selective beta-2-adrenoreceptor agonists | Salbutamol (Albuterol) Terbutaline |
CYP1A2 |
↑ positive inotropic effect of β-sympathomimetics ! reduce/restrict caffeine intake |
Czigle & Tóth (2010b) | ||
| Other systemic drugs for obstructive airway diseases, xanthines | Theophylline | CYP1A2 |
↑ plasma level (23–29%) ↑ adverse reactions ! reduce/restrict caffeine intake |
Carrillo & Benitez (2000), Chrościńska-Krawczyk et al. (2014) | ||
| All other therapeutic products (V03) | Nerve depressants | Ethanol | CYP2D6 |
↑ caffeine plasma level ! reduce/restrict caffeine intake |
Mohamed et al. (2011), Striley & Khan (2014) |
Note:
ATC, Anatomical Therapeutic Chemical Classification System (World Health Organization, 2023); ↑, increase (of); ↓, decrease (of); !, warning; excl., excluding.